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bioRxiv · 10.1101/2020.05.27.119354

PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes

Zaidman, D.·London, N.
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Abstract

Proteolysis-targeting chimeras (PROTACs), which induce degradation by recruitment of an E3 ligase to a target protein, are gaining much interest as a new pharmacological modality. However, designing PROTACs is challenging. Formation of a ternary complex between the protein target, the PROTAC and the recruited E3 ligase is considered paramount for successful degradation. A structural model of this ternary complex could in principle inform rational PROTAC design. Unfortunately, only a handful of structures are available for such complexes, necessitating tools for their modeling. We developed a combined protocol that alternates between sampling of the protein-protein interaction space and the PROTAC molecule conformational space. Application of this protocol - PRosettaC - to a benchmark of known PROTAC ternary complexes results in near-native predictions, with often atomic accuracy prediction of the protein chains, as well as the PROTAC binding moieties. It allowed the modeling of a CRBN/BTK complex that recapitulated experimental results for a series of PROTACs. PRosettaC generated models may be used to design PROTACs for new targets, as well as improve PROTACs for existing targets, potentially cutting down time and synthesis efforts.

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Zaidman, D., London, N.. 2020-05-30. PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes. https://doi.org/10.1101/2020.05.27.119354

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